Fatty acid amide hydrolase (FAAH) is an integral membrane protein that hydrolyzes a wide range of oleyl and arachidonyl amides, the CB1 agonist 2-arachidonylglycerol, the related 1-arachidonylglycerol and 1-oleylglycerol, and methyl arachidonate, illustrating a range of bioactive fatty acid amide or ester substrates. (W. Lang, et al., (1999) J. Med. Chem. 42, 896-902; S. K. Goparaju, et al., (1998) FEBS Lett. 442, 69-73; Y. Kurahashi, et al., (1997) Biochem. Biophys. Res. Commun. 237, 512-515; and T. Bisogno, et al., (1997) Biochem. J. 322,671. Di Marzo, V., T. Bisogno, et al., (1998) Biochem. J. 331,15-19). The distribution of FAAH in the CNS suggests that it also degrades neuromodulating fatty acid amides at their sites of action and is intimately involved in their regulation (E. A. Thomas, et al., (1997) J. Neurosci. Res. 50, 1047-1052). Although a range of fatty acid primary amides are hydrolyzed by the enzyme, FAAH appears to work most effectively on arachidonyl and oleyl substrates (B. F. Cravaft, et al., (1996) Nature 384, 83-87; and D. K. Giang, et al., (1997) Proc. Natl. Acad. Sci. USA 94, 2238-2242). FAAH was referred to as oleamide hydrolase and anandamide amidohydrolase in early studies.
A class of FAAH inhibitor represented by the formula A-B—C has been disclosed by Dale Boger (U.S. Pat. No. 6,462,054). In this formula, A is an α-keto heterocyclic pharmacophore for inhibiting the fatty acid amide hydrolase; B is a chain for linking A and C, said chain having a linear skeleton of between 3 and 9 atoms selected from the group consisting of carbon, oxygen, sulfur, and nitrogen, the linear skeleton having a first end and a second end, the first end being covalently bonded to the α-keto group of A, with the following proviso: if the first end of said chain is an α-carbon with respect to the α-keto group of A, then the α-carbon is optionally mono- or bis-functionalized with substituents selected from the group consisting of fluoro, chloro, hydroxyl, alkoxy, trifluoromethyl, and alkyl; and C is a binding subunit for binding to FAAH and enhancing the inhibition activity of said α-keto heterocyclic pharmacophore, said binding subunit having at least one π-unsaturation situated within a π-bond containing radical selected from a group consisting of aryl, alkenyl, alkynyl, and ring structures having at least one unsaturation, with or without one or more heteroatoms, said bind subunit being covalently bonded to the second end of the linear skeleton of B, the π-unsaturation within the π-bond containing radical being separated from the α-keto group of A by a sequence of no less than 4 and no more than 9 atoms bonded sequentially to one another, inclusive of said linear skeleton.
What is needed are FAAH inhibitors having a head group attached to a tail region, the head group having one or more heterocycles for achieving enhanced activity with respect to the inhibition of fatty acid amide hydrolase.